Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites

Lalovic, Bojan; Kharasch, E. D.; HOFFER, C; Risler, Linda J.; LIUCHEN, L; Shen, Danny D.

doi:10.1016/j.clpt.2006.01.009

Cited by 390 publications

(488 citation statements)

References 46 publications

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“…The mechanism behind this interaction might be the induction in lamotrigine glucuronidation [48]. Theoretically, the induction of glucuronidation could have an influence on the metabolism of oxycodone and its metabolites, but these metabolic routes are of minor importance [49] and they were not investigated in this study. Additionally, it is unlikely, that short duration of ritonavir would have induced the glucuronidation of noroxycodone and oxymorphone significantly.…”

Section: Pharmacodynamic Resultsmentioning

confidence: 99%

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Nieminen

Hagelberg

Saari

et al. 2010

Eur J Clin Pharmacol

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To cite this version:Methods: A randomized crossover study design with 3 phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioural effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis.Results: Ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-(range 1.9-to 4.3-fold; P<0.001) and 2.6-fold (range 1.9-to 3.3-fold; P<0.001). The mean (± SD) elimination half-life prolonged after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P<0.001) and 5.7 ± 0.9 h (P<0.001), respectively. Both ritonavir (P<0.001) and lopinavir/ritonavir (P<0.05) increased the self-reported drug effect of oxycodone. Conclusions:Ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse-effects.

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Section: Pharmacodynamic Resultsmentioning

confidence: 99%

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Nieminen

Hagelberg

Saari

et al. 2010

Eur J Clin Pharmacol

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“…The main known metabolic pathways of oxycodone are through O ‐demethylation to oxymorphone via CYP2D6 and through N ‐demethylation to noroxycodone via CYP 3A4 (Lalovic et al. 2006; Gronlund et al. 2011; Naito et al.…”

Section: Introductionmentioning

confidence: 99%

Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

Li¹,

Sun

Palmisano³

et al. 2016

Pharmacology Res & Perspec

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Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate‐release or controlled‐release formulations, under different administration routes, and in diverse populations. Longer terminal half‐lives from extravascular administration as compared to IV administration have been attributed to flip‐flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip‐flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time‐varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half‐lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate‐dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. It showed no actual drug absorption during the terminal phase, but slower drug clearance caused by slower release/absorption producing the appearance of flip‐flop and offered new insight for the development of modified release formulations and clinical use of oxycodone.

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“…The predominant metabolic pathway of oxycodone is CYP3A4-mediated Ndemethylation to noroxycodone, while a small part of the oxycodone undergoes 3-O-demethylation to oxymorphone by CYP2D6 [5,6]. Further oxidation of these metabolites via CYP2D6 (and CYP3A4) yields noroxymorphone [5,6]. Although the metabolites possess μ-opioid receptor activity, the relative contribution of the different metabolites to the central opioid effects are still to discussion [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Only 10% of the oxycodone dose is excreted unchanged in the urine [2][3][4][5]. The predominant metabolic pathway of oxycodone is CYP3A4-mediated Ndemethylation to noroxycodone, while a small part of the oxycodone undergoes 3-O-demethylation to oxymorphone by CYP2D6 [5,6]. Further oxidation of these metabolites via CYP2D6 (and CYP3A4) yields noroxymorphone [5,6].…”

Section: Introductionmentioning

confidence: 99%

Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

Saari

Grönlund

Hagelberg

et al. 2010

Eur J Clin Pharmacol

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Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites

Abstract: CYP3A-mediated N-demethylation is the principal metabolic pathway of oxycodone in humans. The central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites.

Cited by 390 publications

References 46 publications

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

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